Mucolipidosis type IV (MLIV; MIM 252650) is an autosomal recessive developmental disorder with abnormal brain, eye and gastric functions. It was first described by Berman et al. (J. Pediat. 1974, 84:519–26) who studied an Ashkenazi Jewish infant with corneal clouding, a variety of storage bodies and large vacuoles in many different cell types, in the presence of normal levels of lysosomal hydrolases. The lack of identification of a specific storage compound led to the mucolipidosis classification.
Clinically, MLIV is characterized by a variable degree of growth and psychomotor retardation that is apparent as early as the first year of life. Most patients are unable to speak or walk independently and remain developmentally at a 1–2 year level. Patient head MRI at the time of diagnosis shows a dysplastic corpus callosum and dysmyelinating white matter abnormalities indicating early onset of brain pathology, while cerebellar atrophy is seen predominantly in older patients (Frei et al., Neurology 1998, 51:565–9). MLIV is further characterized by corneal clouding and a progressive retinopathy with optic atrophy, which results in severe visual impairment (Reidel et al., Am. J. Ophthalmol. 1985, 99:125–36). The majority of MLIV patients appear to have a static encephalopathy and do not deteriorate neurologically; however, some patients show a decline in motor function in the second or third decade of life. A simple approach to the diagnosis of MLIV was obtained when we discovered that all patients have constitutive achlorhydria associated with a secondary elevation of serum gastrin levels (Schiffman et al., Proc. Natl. Acad. Sci. 1998, 95:1207–12). At the present time, MLIV is the only genetic disease known to be associated with elevated gastrin.
The gene that is mutated in MLIV, MCOLN1 has been mapped to a 5.6 cM region on chromosome 19p13.2–13.3 by linkage analysis in 26 Ashkenazi Jewish (AJ) families (Slaugenhaupt et al., Am. J. Human Genet. 1999, 65:773–8). In addition, the ethnic bias seen in MLIV is apparently due to a founder effect, with two common haplotypes representing 96% of the chromosomes. Utilizing the finding that the storage bodies in MLIV fibroblasts are autofluorescent (Goldin et al., Pediat. Res. 1995, 37:687–92), a single gene defect in both AJ and non-Jewish (NJ) patients (Goldin et al., Proc. Natl. Acad. Sci. 1999, 96:8562–6), was implicated by complementation assays. However, there remained a need to identify a specific gene involved in this disease.